Highly active antiretroviral therapy (HAART) has been shown to decrease plasma and CSF viral load, delay the onset of immunosuppression and improve cognitive function in HIV-infected individuals. However, HAART has been less effective in lowering virus replication in the CNS as demonstrated by studies showing modest to no reduction in CSF viral load in patients on HAART despite dramatic reductions in plasma virus load. Further, two comprehensive autopsy studies of 740 HIV-infected individuals found no change in the incidence of CNS inflammatory lesions since 1996, when HAART was first introduced. These data suggest that antiretroviral therapy does not completely suppress virus replication in the CNS, nor the accompanying inflammatory changes. It is difficult to comprehensively examine the effects of antiretroviral therapy on CNS virus replication and inflammation in HIV-infected individuals because early and ongoing events in the CNS cannot be directly examined. The SIV/macaque model is an ideal system in which to examine the effects of antiretroviral therapy on the CNS during both acute and long term infection. The proposed studies will determine, in an SIV model that consistently causes SIV encephalitis, whether antiretroviral therapy that effectively suppresses systemic virus replication also suppresses CNS virus replication and inflammation. Our hypothesis is that antiretroviral therapy that effectively lowers viral load in the periphery does not abrogate virus replication or the accompanying inflammatory changes in the CNS. Our Aims are: 1 a ) To determine whether CNS virus replication is suppressed in macaques treated with antiretroviral therapy that effectively suppresses plasma viral load. 1 b) To determine whether antiretroviral therapy that suppresses plasma viral load also suppresses virus replication in specific target cells in the CNS, including macrophages, microglia, lymphocytes, astrocytes, and neurons. 1 c) To determine whether antiretroviral therapy that suppresses plasma viral load also suppresses CNS inflammation in the brains of SIV-infected macaques as measured by infiltration of macrophages into the CNS, activation of astrocytes and microglial cells, and production of chemokines and expression cell adhesion molecules on endothelial cells. 2) To determine whether antiretroviral therapy that suppresses virus replication in the periphery modulates the selection and replication of neurovirulent viruses in the CNS of SIV-infected macaques.